This invention relates to a phosphonylating agent and phosphonylation conditions that are mild and promote a regioselective, reproducible conversion of an hydroxy moiety to the corresponding phosphonate derivative. The phosphonylating agents and conditions may be used for preparing derivatives of pharmaceutical compounds which have improved stability and water solubility. For example, this invention may be used to make derivatives of various cyclic peptide compounds which are used as antifungal and antiparasitic agents.
In general, the cyclic peptides are unstable under basic conditions. Specifically, the presence of a base causes ring opening and decomposition of the cyclic peptide. In addition, the cyclic peptides are sensitive to strong acids. A popular strategy for phosphonylating the hydroxy moiety of a compound involves the use of an alkyl phosphonic dichloride as the phosphonylating agent. However, a by-product of the hydrolytic work-up of the reaction is hydrochloric acid. The reaction is typically carried out in the presence of a base which both promotes the phosphonylation reaction and acts as an acid scavenger. This reaction has limited usefulness with respect to the cyclic peptides as a result of poor yields due to the sensitivity of the nucleus to both base andacid. In addition, alkyl phosphonic dichloride reagents are very reactive and not regioselective for reaction at only the desired phenolic oxygen of the polyfunctional cyclic peptides.
The cyclic peptides are produced by fermentation of various microorganisms. A number of cyclic peptides are known in the art including echinocandin B (A30912A), aculeacin, mulundocandin, sporiofungin, L-671,329, and S31794/F1. In general, these cyclic peptides may be structurally characterized as a cyclic hexapeptide core (or nucleus) with an acylated amino group on one of the core amino acids. The amino group is typically acylated with a fatty acid group forming a side chain off the nucleus. For example, echinocandin B has a linoleoyl side chain while aculeacin has a palmitoyl side chain. The fatty acid side chains may be removed from the cyclic peptide core to provide an amino nucleus (for example, a compound of formula II, below, where R.sub.2 is hydrogen). The amino group may then be re-acylated to provide semi-synthetic compounds which may be phosphonylated according to the present invention.
Examples of echinocandin compounds that may be converted to the corresponding phosphonate derivatives include compounds of formula IIB: ##STR1## wherein: R' is hydrogen, methyl or NH.sub.2 C(O)CH.sub.2 --;
R" and R'" are independently methyl or hydrogen; PA1 R.sup.x1, R.sup.x2, R.sup.y1, R.sup.y2, R.sup.y3, and R.sup.y4 are independently hydroxy or hydrogen; and PA1 R.sub.2 is an acyl side chain as defined herein. PA1 R.sup.1 is phenyl, naphthyl, cyclohexyl or a compound of the formula ##STR3## where R.sup.1a is hydrogen, halo, trifluoromethyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, nitro, protected amino, phenyl, benzyl or benzyloxy; with the proviso that when R.sup.1 is ##STR4## then R.sup.1a cannot be hydroxy, C.sub.1 -C.sub.6 alkoxy or benzyloxy; or a pharmaceutically acceptable salt thereof PA1 R" and R'" are independently methyl or hydrogen; PA1 R.sup.x1, R.sup.x2, R.sup.y1, R.sup.y2, R.sup.y3, and R.sup.y4 are independently hydroxy or hydrogen; PA1 R is C.sub.1 -C.sub.6 alkyl, phenyl or benzyl; PA1 Z is --CH.sub.2 --R.sup.1 ; PA1 R.sup.1 is phenyl, naphthyl, cyclohexyl or a compound of the formula ##STR6## where R.sup.1a is hydrogen, halo, trifluoromethyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, nitro, protected amino, phenyl, benzyl or benzyloxy; PA1 R.sub.2 is acyl; PA1 R" and R'" are independently methyl or hydrogen; PA1 R.sup.x1, R.sup.x2, R.sup.y1, R.sup.y2, R.sup.y3 and R.sup.y4 are independently hydroxy or hydrogen; PA1 R is C.sub.1 -C.sub.6 alkyl, phenyl or benzyl; PA1 Z is hydrogen or --CH.sub.2 --R.sup.1 ; PA1 R.sup.1 is phenyl, naphthyl, cyclohexyl or a compound of the formula ##STR9## where R.sup.1a is hydrogen, halo, trifluoromethyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, nitro, protected amino, phenyl, benzyl or benzyloxy; PA1 R.sub.2 is acyl; PA1 a) reacting a compound of formula I ##STR11## with a compound of formula IIB ##STR12## in the presence of a base at a temperature of from about -30.degree. C. to about 40.degree. C. to provide a compound of formula II; PA1 b) optionally converting the compound of formula II to provide the compound of formula IIA where Z is hydrogen; and PA1 c) optionally forming a pharmaceutically acceptable salt. PA1 R" and R'" are independently methyl or hydrogen; PA1 R.sup.x1, R.sup.x2, R.sup.y1, R.sup.y2, R.sup.y3, and R.sup.y4 are independently hydroxy or hydrogen; PA1 R is C.sub.1 -C.sub.6 alkyl, phenyl or benzyl; PA1 Z is --CH.sub.2 --R.sup.1 ; PA1 R.sup.1 is phenyl, naphthyl, cyclohexyl or a compound of the formula ##STR14## where R.sup.1a is hydrogen, halo, trifluoromethyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, nitro, protected amino, phenyl, benzyl or benzyloxy; PA1 R.sub.2 is acyl; PA1 Z is hydrogen, PA1 1) hydrogenating the compound of formula II by PA1 2) optionally forming a pharmaceutically acceptable salt. PA1 B) R.sub.3 is --O--(CH.sub.2).sub.m --[O--(CH.sub.2).sub.n ].sub.p --O--(C.sub.1 -C.sub.12 alkyl); PA1 C) R.sub.3 is --Y--(C.sub.1 -C.sub.12 alkyl); PA1 D) R.sub.3 is --O--(CH.sub.2).sub.q --G; PA1 A) R.sub.4 is hydrogen, C.sub.1 -C.sub.12 alkyl, C.sub.1 -C.sub.12 substituted alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 substituted alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.2 -C.sub.12 substituted alkynyl, C.sub.1 -C.sub.12 alkoxy, C.sub.3 -C.sub.12 cycloalkyl, C.sub.7 -C.sub.10 bicycloalkyl, C.sub.7 -C.sub.14 tricycloalkyl, C.sub.3 -C.sub.12 cycloalkoxy, naphthyl, pyridyl, thienyl, benzothienyl, quinolyl or phenyl; or PA1 B) R.sub.4 is phenyl substituted by amino, C.sub.1 -C.sub.12 alkylthio, halo, C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.1 -C.sub.12 substituted alkyl, C.sub.2 -C.sub.12 substituted alkenyl, C.sub.2 -C.sub.12 substituted alkynyl, C.sub.1 -C.sub.12 alkoxy, trifluoromethyl, phenyl, substituted phenyl, or phenyl substituted with a group of the formula --O--(CH.sub.2).sub.m --[O--(CH.sub.2).sub.n ].sub.p --O--(C.sub.1 -C.sub.12 alkyl) where m, n and p are as defined above; or PA1 C) R.sub.4 is C.sub.1 -C.sub.12 alkoxy substituted with halo, C.sub.3 -C.sub.12 cycloalkyl, C.sub.7 -C.sub.10 bicycloalkyl, C.sub.7 -C.sub.14 tricycloalkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.12 alkynyl, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, formamido, C.sub.2 -C.sub.12 alkanoylamino, or phenyl substituted with a group of the formula --O--(CH.sub.2).sub.m --[O--(CH.sub.2).sub.n ].sub.p --O--(C.sub.1 -C.sub.12 alkyl) where m, n and p are as defined above; or PA1 D) R.sub.4 is --O--(CH.sub.2).sub.r --W--R.sub.5 ; PA1 E) R.sub.4 is --Y.sup.1 --R.sub.6 ; PA1 F) R.sub.4 is C.sub.1 -C.sub.12 alkoxy substituted with a group of the formula --NHC(O)R.sub.7 ; PA1 R.sub.9 is phenyl, C.sub.1 -C.sub.12 alkyl, or C.sub.1 -C.sub.12 alkoxy; or PA1 A) R.sub.4 is hydrogen, C.sub.1 -C.sub.12 alkyl, C.sub.1 -C.sub.12 substituted alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 substituted alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.2 -C.sub.12 substituted alkynyl, C.sub.1 -C.sub.12 alkoxy, C.sub.3 -C.sub.12 cycloalkyl, C.sub.7 -C.sub.10 bicycloalkyl, C.sub.7 -C.sub.14 tricycloalkyl, C.sub.3 -C.sub.12 cycloalkoxy, naphthyl, pyridyl, thienyl, benzothienyl, quinolyl or phenyl; or PA1 B) R.sub.4 is phenyl substituted by amino, C.sub.1 -C.sub.12 alkylthio, halo, C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.1 -C.sub.12 substituted alkyl, C.sub.2 -C.sub.12 substituted alkenyl, C.sub.2 -C.sub.12 substituted alkynyl, C.sub.1 -C.sub.12 alkoxy, trifluoromethyl, phenyl, substituted phenyl, or a group of the formula --O--(CH.sub.2).sub.m --[O--(CH.sub.2).sub.n ].sub.p --O--(C.sub.1 -C.sub.12 alkyl) where m, n and p are as defined above; or PA1 C) R.sub.4 is C.sub.1 -C.sub.12 alkoxy substituted with halo, C.sub.3 -C.sub.12 cycloalkyl, C.sub.7 -C.sub.10 bicycloalkyl, C.sub.7 -C.sub.14 tricycloalkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.12 alkynyl, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino formamido, C.sub.2 -C.sub.12 alkanoylamino, or phenyl substituted with a group of the formula --O--(CH.sub.2).sub.m --[O--(CH.sub.2).sub.n ].sub.p --O--(C.sub.1 -C.sub.12 alkyl) where m, n and p are as defined above; or PA1 D) R.sub.4 is --O--(CH.sub.2).sub.r --W--R.sub.5 ; PA1 E) R.sub.4 is --Y.sup.1 --R.sub.6 ; PA1 F) R.sub.4 is C.sub.1 -C.sub.12 alkoxy substituted with a group of the formula --NHC(O)R.sub.7 ; PA1 R is C.sub.1 -C.sub.4 alkyl; PA1 R.sup.1 is phenyl or a compound of the formula ##STR24## where R.sup.1a is hydrogen, halo, C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.6 alkoxy; or a pharmaceutically acceptable salt thereof. PA1 R is methyl; PA1 R.sup.1 is phenyl or a compound of the formula ##STR25## where R.sup.1a is halo or hydrogen; or a pharmaceutically acceptable salt thereof. PA1 R.sup.1 is phenyl or a compound of the formula ##STR26## where R.sup.1a is bromo or hydrogen; or a pharmaceutically acceptable salt thereof.
Such cyclic peptides are useful antifungal and antiparasitic agents due to their biological activity against these pathogens. These compounds may be used as oral, topical or intravenous (iv) drugs. However, these compounds are not well-suited for intravenous formulation due to their relatively poor aqueous solubility. Yet, an iv formulation is particularly desirable when the drug is to be used with a patient who is unable to take it orally, for example because the patient is immunocompromised, or when it is necessary to obtain high levels of compound systemically, for example when treating a systemic infection, an organ infection such as hepatosplenic infection or an iv catheter candida infection.
The development of an antifungal or antiparasitic drug using these compounds necessitates increasing the aqueous solubility of the compounds using either formulation technology or by the development of a suitable prodrug. With respect to the latter, it has been discovered that the phosphonic acid derivatives of the various cyclic peptides have properties that are desirable for effective prodrugs. Specifically, the echinocandins may be converted to a phosphonic acid prodrug by phosphonylating the phenolic hydroxy of the homotyrosine moiety and then deprotecting the resultant phosphonate to provide the desired phosphonic acid derivative.
The present invention provides a phosphonylating agent and phosphonylation conditions that are compatible with the sensitive cyclic peptide nucleus and promote a clean and reproducible conversion to a phosphonate derivative. The phosphonylation conditions are selective for phosphonylation at the homotyrosine moiety.
The present invention also provides intermediate compounds useful in preparing the phosphonate derivatives of these cyclic peptides and a process for preparing the desired phosphonic acid derivatives.